Antipsychotics

Dr. Pagan Pambudi, M.Si, Sp.S

 Schizophrenia
• Schizophrenia is a chronic heterogeneous
syndrome of disorganized and bizarre
thoughts, delusions, hallucinations,
inappropriate affect, cognitive deficits, and
impaired psychosocial functioning.
DA Theory of Schizophrenia and other
disorders
• Dopaminergic hypothesis. Psychosis may result
from hyper- or hypoactivity of dopaminergic
processes in specific brain regions. This may
include the presence of a dopamine (DA)
receptor defect.
• Positive symptoms (see Diagnosis section
below) may be more closely associated with
DA receptor hyperactivity in the mesocaudate,
while negative symptoms and cognitive
symptoms may be most closely related to DA
receptor hypofunction in the prefrontal cortex.
Dopamine Projection
Dopamine receptor
 Receptor on Target in psychotics
disorders
FGA (D2) SGA (D2/5HT2A/C)
• Chlorpromazine • Clozapine
• Haloperidol • Olanzapine
• Stelazine • Risperidone
• Fluphenazine • Quetiapine
• Thioridazine • Ziprasidone
• Perphenazine • Aripirazole
• Molindone
• Pimozide
 SGA
• Second-generation antipsychotic drugs are
characterized by the following criteria:
– few or no EPS; significant reduction in tardive
dyskinesia liability compared to first-generation
antipsychotics
– expanded spectrum of therapeutic efficacy
– less prolactin elevation
 Indication of antipsychotics
• Schizophrenia and Schizoaffective Disorder
• Acute manic and mixed episodes of bipolar disorder
• Major depression with psychosis
• Delusional disorder
• Delirium
• Dementia
• Mental retardation
• Developmental disorders (e.g., Autism)
• Huntington’s disease
• Tourette’s syndrome
• Substance-induced psychoses (psychostimulants,
phencyclidine, levodopa, steroids)
 Consequences of D2 blockade
• Decrease psychotics positive symptoms
• Development of EPS if > 80% D2 receptor
occupancy
• Development of hyperprolactinemia
 Consequences of 5HT2A antagonism
• Increase DA prefrontal  alleviate negative
symptoms
• Decrease EPS
 Other receptor involved
• Histamin
• Muscarinic acetylcholin
• Alpha adrenergic
 Chlorpromazine
• Alters effects of dopamine (D2 ) in CNS. Has
significant anticholinergic/alpha-adrenergic blocking
activity  high evidence of orthostatic medication
• Variable absorption from tablets/suppositories; better
with oral liquid formulations. Well absorbed
following IM administration.
• Distribution: Widely distributed; high CNS
concentrations. Crosses placenta; enters breast milk.
• Metabolism and Excretion: Highly metabolized by
liver and GI mucosa. Some metabolites are active.
 Chlorpromazine
• Dosage:
– ADULT: usual dosage 200 mg – 1g/day oral
– Child: 0,55 mg/Kg/BB/ day max 40 mg/day

• Orthostatic hypotension is frequent when

using injection
 Haloperidol
• Strong D2 blockers
• Absorption: Well absorbed following PO/IM
administration. Decanoate salt absorbed slowly
and has a long duration of action
• Distribution: Concentrates in liver. Crosses
placenta; enters breast milk.
• Metabolism and Excretion: Mostly metabolized
by liver.
• Protein Binding: 90%.
• T 1/2: 21–24 hr.
 Haloperidol
DOSAGE
• PO (Adults): 0.5–5 mg two to three times daily. Clients with severe
symptoms may require up to 100 mg/day.
• PO (Geriatric Clients or Debilitated Clients): 0.5–2 mg twice daily
initially; may be gradually increased as needed.
• PO (Children 3–12 yr or 15–40 kg): 50 mcg/kg/day in two to three
divided doses; may increase by 500 mcg (0.5 mg)/day every 5–
7 days as needed (up to 75 mcg/kg/day for nonpsychotic
disorders or Tourette’s syndrome or 150 mcg/kg/day for
psychoses).
• IM (Adults): 2–5 mg every 1–8 hr (not to exceed 100 mg/day).
• Haloperidol Decanoate: IM (Adults): 10–15 times the previous daily
PO dose but not to exceed 100 mg initially, given monthly (not to
exceed 300 mg/mo).
 Haloperidol
Preparation
• Tablets: 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 20
mg. Oral concentrate: 2 mg/mL.
• Haloperidol injection: 5 mg/mL.
• Haloperidol decanoate injection: 50 mg/mL,
100 mg/mL.
 Fluphenazine
• Absorption: Well absorbed after PO/IM
administration.
• Decanoate salt in sesame oil has delayed
onset and prolonged action because of
delayed release from oil vehicle and
subsequent delayed release from fatty tissues
 depot preparation
 Fluphenazine
• Distribution: Widely distributed. Crosses
blood-brain barrier. Crosses placenta; enters
breast milk.
• Metabolism and Excretion: Highly
metabolized by liver; undergoes
enterohepatic recirculation.
 Fluphenazine
• Dosage: Fluphenazine Decanoate: IM (Adults):
12.5–25 mg initially; may be repeated every 3
wk. Dosage may be slowly ↑ as needed (not
to exceed 100 mg/dose).
• Fluphenazine Hydrochloride: PO (Adults):
0.5–10 mg/day in divided doses every 6–8
hr (maximum dose = 40 mg/day).
 Risperidone
• SGA with 5HT2A antagonism properties
• MOA: D2, 5HT2A antagonist
• Absorption: 70% oral
– Following IM administration, small initial release
of drug, followed by 3–week lag; rest of release
starts at 3 weeks and lasts 4–6 weeks.
• Extensively metabolized by liver. Metabolism
genetically determined
• Excretion renally
 Risperidone dosage
• Schizophrenia: PO (Adults): 1 mg twice daily,
↑ by 1–2 mg/day no more frequently than
every 24 hr to 4–8 mg daily. PO (Children 13–
17 yr): 0.5 mg once daily, ↑ by 0.5–1 mg no
more frequently than every 24 hr to 3 mg
daily.
• IM (Adults): 25 mg every 2 weeks; some
clients may require larger dose of 37.5 or 50
mg every 2 weeks.
 Clozapine
• SGA
• MOA: act on D2, 5 HT, anticholinergic, alp-1
antagonist
• Lack of EPS, but risk of hematological problems
• Well absorbed after oral administration.
Distribution: Rapid and extensive distribution;
crosses blood-brain barrier and placenta.
• Excretion: excretion renal
• Protein bindings: 95%
 Clozapine dosage
• PO (Adults): 25 mg 1–2 times daily
initially; ↑ by 25–50 mg/day over 2 wk up
to target dose of 300–450 mg/day. May ↑ by
up to 100 mg/day once or twice further (not
to exceed 900 mg/day
 Aripiprazole
• Partial agonist activity at dopamine D2 and sero-tonin
5-HT1A receptors and antagonist activity at the 5-HT2A
receptor. Also has alpha-1 adrenergic blocking activity.
• Starting and target dose: 10 or 15 mg/day as a single
dose; doses up to 30 mg/day have been used;
increments in dosing should not be made before 2 wk
at a given dose.
• PO (Adults and Children 13–17 yr): Starting and target
dose: 2 mg/day as a single dose, then titrated up for
5 days to a target dose of 10 mg/day. Maximum
dose 30 mg/day.
Clinical Profile Comparison between SGA
SGA Dosage
 Pharmacokinetics consideration
• All antipsychotics is metabolized in liver by
CYP-450 consider drugs-interaction:
– Drugs that inhibit CYP-450  increase
antipsychotics avaibility
• SSRI’s, ketoconazole, erytromycin, valproic acid
– Drugs that induce CYP-450, decrease
antipsychotics vaibility
• Phenytoin, carbamazepine, barbiturates, rifampin
 Antipsychotics side effect
• Acute Extrapyramidal Side Effects
– Distonia, parkinsonism, Akathisia
– occur both acutely and after chronic treatment
– FGA >>SGA, Clozapine and quetiapine has the
minimal risk or zero risk for clozapine because of
relatively low D2 afinity and/or 5HT2A antagonism
– Occurs as D2 antagonism consequences, if more
than 80% D2 occupancy
– Treat by diphenhidramine, if use FGA switch to
SGA, or combine with THD
Receptor affinities
 Antipsychotics side effect
• Tardive Dyskinesia and Other Tardive
Syndrome
– choreiform movements, tics and grimaces of
the oro-facial muscles, and dyskinesia of distal
limbs, often the paraspinal muscles, and occasion-
ally the diaphragm.
– increased with emotional arousal and are absent
when the individual is asleep.
– exposure to antipsychotic drugs should have
totaled at least three months
 Antipsychotics side effect
• Tardive Dyskinesia and Other Tardive
Syndrome
– approximately 20% of patients who receive
chronic treatment, exceed 50% in high-risk
groups, such as the elderly.
– High risk of TD are older age, female gender, pres-
ence of EPS, diabetes mellitus, affective disorders
 Antipsychotics side effect
HYPERTHERMIA

Increase creatin
kinase > 300 U/ml Leucocytosis > 15000

NMS
RIGIDITY AUTONOMIC
INSTABILITY
 Endocrine and Sexual Effects
• Hyperprolactinemia
– High: Risperidone, amilsupride
– Moderate: FGA
– Low: Clozapine, olanzapine, quetiapine,
ziprasidone
– None: aripiprazole
 Endocrine and Sexual Effects
• Hyperprolactenemia can cause:
– Woman:
• menstrual disturbances,
• including anovulatory cycles and infertility,
• menses with abnormal luteal phases,
• frank amenorrhea and hypoestrogenemia.
• decreased libido and anorgasmia
• Ginecomastia
• Galactorhea
 Endocrine and Sexual Effects
Hyperprolactenemia can cause:
• Man
– loss of libido, impotence, hypospermatogenesis,
– and erectile or ejaculatory disturbances.
– Ginecomastia
– Galactorrhea
 Metabolic Effect
Weight gain Blood glucose Lipids Blood pressure
Clozapine Clozapine Clozapine Clozapine
Olanzapine Olanzapine Olanzapine Olanzapine
Risperidone Quetiapine
Risperidone
FGA low potency

Free of Metabolic side effect:

•Aripiprazole
•Ziprazidone
 Cardiovascular effect
• Orthostatic hypotension • EEG abnormalities
– Low potency FGA – Chlorpromazine
– Clozapine, Olanzapine – Ziprasidone
– Thioridazine
• Tachycardia
– Chlorpromazine • Malignat arrythmia
– Clozapine – Ziprasidone
– quetiapine • Cardiomyopathy
– Clozapine
 Gastrointestinal and hepatic SE
• Gi abnormality due to anticholinergic effect
– Dry mouth, constipation, paralytic ileus
– Low potency FGA, clozapine, olanzapine

• Transaminase elevation slightly occurs in all

antipsychotics, jaundice rarely
 Hematological SE
• blood dyscrasias, including neutropenia,
leukopenia, leukocytosis, thrombopenia,
and agranulocytosis
– CPZ
– Clozapine (agranulocytosis)
• Usually reversible after discontinuation
 Other SE
• Sedation
– Low potency FGA
– Clozapine
– Olanzapine
– Quetiapine
• Seizure
– Generally all antipsychotics lower the seizure
threshold
– Clozapine is the most
 Antipsychotics in pregnancy
and breast feeding
• Consider in 1st semester
• 2nd and 3rd relatively save
• If using FgA use the high potency class
• There is no evidence that second-generation
antipsychotics are teratogenic in humans
• Do not breast feeding during antipsychotics
medication
Guideliness in managing Schizophrenia

First episode: try SGA

Try other SGA or FGA

Clozapine

Clozapine + FGA or SGA or ECT

Other SGA or FGA not use in step

1,2
 Guideliness in managing
Schizophrenia

Combination Therapy
e.g., SGA + FGA, combination
of SGAs, (FGA or SGA) + ECT, (FGA or SGA)
+ other agent (e.g., mood stabilizer)

The Texas Medication Algorithm Project antipsychotic algorithm for

schizophrenia: 2006 update. J Clin Psychiatry 2007;68:1751–1762.)
 Cost
• Hence, despite the near-total switch to the
second-generation antipsychotics and the
tremendous increase in costs, the overall
advantages of the second-generation to the
first-generation antipsychotics appear minor.
 Depot Antipsychotic Medications
• Adherence to drugs is a big problems in
maintaining psychotic patients
• Depot is the answer of this problems
– Haloperidol decanoate (haldol decanote)
• 50 mg monthly, Z track IM
– Risperidone (Risperdal Consta)
• 25-50 mg 2 weely
– Fluphenazine decanoate
• 12,5-25 mg 4-6 weekly
Thanks